The erectile dysfunction drug Viagra could soon be recommended as a therapy to decrease the risk of Alzheimer’s disease and help reduce the alarming rise in dementia cases worldwide, suggests a recent study, confirming some previous findings.
By analysing medical insurance data alongside a laboratory investigation on the genetic and neurological effects of sildenafil – commonly sold under the brand name Viagra – researchers in the US have validated the medication’s potential in keeping critical proteins in nerve cells from tangling into a deadly mess.
Studies have repeatedly demonstrated that enzyme blockers, called phosphodiesterase (PDE) inhibitors, not only have an ability to promote blood flow in the penis, but could prevent the neurodegeneration responsible for dementia.
This potential might not be all that surprising, given PDEs are known to be involved in nerve signalling pathways that influence neuroplasticity, reports ScienceAlert. Previous investigations on animal models have shown the PDE inhibitor sildenafil reduces the excessive phosphorylation of tau proteins in nerve cells that causes them to form toxic tangles, helping improve cognitive health and memory.
Yet not all research has been so flattering, with some studies failing to notice an effect on the population level at all. And while the drugs may have an effect on a neurological level, the mechanisms behind this process still aren’t fully understood.
In the latest findings, published in the Journal of Alzheimer’s Disease, researchers used cell cultures of neurons created from stem cells donated by Alzheimer’s patients to map the metabolic and genetic activity behind sildenafil’s therapeutic effects.
After five days of treatment, the laboratory-grown neurons produced significantly lower levels of tau proteins with excess concentrations of phosphorus added, confirming sildenafil’s knack for protecting brain cells.
A reading of the messages produced by the cells’ DNA found hundreds of changes in the expression of genes, many involving the inflammation, breakdown in communication between nerves, and guidance of nerve cell structures.
While additional studies will be needed to pinpoint exactly how these subtle influences may be involved in the pathology behind Alzheimer’s, understanding the main gene families affected by sildenafil provided a solid foundation for understanding why it works and perhaps why some brains develop Alzheimer’s in the first place.
A second feature of the study used AI to look for signs of sildenafil working on a population level. Previous studies have used medical insurance data to find sildenafil can reduce the risk of Alzheimer’s disease by around 60%.
Yet these relied on just a single insurance database, potentially missing out on variables that might reveal a different conclusion.
What’s more, these studies suggested patients being treated for high blood pressure in the lungs, or pulmonary hypertension (PH), didn’t see the same drop in dementia risk.
The researchers included four treatments commonly prescribed for PH in their data analysis, not only confirming sildenafil decreased Alzheimer’s risk by around 60%, but finding it reduced risk in people with pulmonary hypertension after all.
“After integrating this large amount of data computationally, it is rewarding to see sildenafil’s effects in human neurons and real-world patient outcomes,” said Cleveland Clinic biomedical informatician and co-first author Feixiong Cheng.
“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease.”
With sildenafil already given the FDA tick of approval for erectile dysfunction, demonstrating its safety and effectiveness in reducing Alzheimer’s risk could provide health authorities with a quick means of addressing what looks to be a rising tide of dementia.
Ageing populations worldwide can expect the number of people with dementia to nearly double every 20 years, from just under 80m at the end of this decade to nearly 140m by mid-century.
If we already have a pill at hand that can keep these numbers down, research like this will be vital in proving its worth.
Study details
Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons
Gohel, Dhruva, Zhang, Pengyueb, Gupta, Amit Kumara, Cheng, Feixiongam et al.
Published in the Journal of Alzheimer’s Disease on 19 March 2024
Abstract
Background
Alzheimer’s disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD.
Objective
To investigate the potential therapeutic benefit of sildenafil on AD.
Methods
We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil’s mechanism-of-action.
Results
We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32– 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49– 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD.
Conclusions
These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomised clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.
ScienceAlert article – Huge study confirms viagra cuts alzheimer's risk by over 50% (Open access)
See more from MedicalBrief archives:
Viagra linked to lower Alzheimer’s risk – UK study
Viagra as a candidate drug for Alzheimerʼs disease — US prescription analysis
Up to half of men under 50 suffer from erectile dysfunction